Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5 % of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a ‘three-hit’ process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 have been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may results in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 are more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 are up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major drug metabolizing enzymes and transporters. We also discuss the potential mechanisms underlying these alterations.

Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of sedative alcohol actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0mg b.i.d., 50mg b.i.d., 100mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss of righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.

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In this work the binding of V^IVO²⁺ and V^IVO-complexes to serum albumins {human serum albumin (HSA), bovine serum albumin (BSA) and porcine serum albumin (PSA)} are studied using circular dichroism (CD), electron paramagnetic resonance (EPR) and visible absorption spectroscopy. The results confirm previous findings that V^IVO²⁺ occupies at least two types of binding sites on albumin: ‘the strong vanadium binding site’ (designated by VBS1) and ‘the weak vanadium binding sites’ (designated by VBS2). VBS1 binds 1 mol equivalent of V^IVO²⁺. On the other hand VBS2 correspond to binding of several mol equivalents of V^IVO, and studies done with PSA in the presence of excess Zn^II ions indicate that VSB2 corresponds to two distinct types of sites. The hyperfine coupling constant A_z for V^IVO²⁺ binding at VBS2 on HSA and BSA are all very similar (~168 × 10-4 cm^-1) but differ slightly on PSA (~166 × 10-4 cm^-1) due to differences in the binding sets. When (V^IVO)-HSA systems are titrated with maltol ternary species of (maltol)_m(V^IVO)_mHSA and (maltol)_2m(V^IVO)_mHSA stoichiometry form which are clearly distinguishable from the binary (V^IVO)-HSA system by the type and intensity of the CD spectra recorded. Changes are also observable in the intensity of the X-band EPR spectra, but not much in the hyperfine coupling constants A_z, which are all in the range 166-167 × 10-4 cm^-1. The results further demonstrate that the presence of maltol may enhance the binding of VIVO to albumin.

Background Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder (AUD). Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals. Methods This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included two experimental alcohol administration paradigms: intravenous alcohol self-administration (IV-ASA) and intravenous alcohol clamp (IV-AC). Each paradigm consisted of two counterbalanced sessions of IV ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), gastric inhibitory peptide (GIP), insulin, insulin-like growth factor-1 (IGF-1), cortisol, prolactin, and aldosterone. Results Despite some statistical differences, findings were consistent across the two alcohol administration paradigms: IV ghrelin, compared to placebo, increased blood concentrations of GLP-1, PP, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin versus placebo session. Conclusion These findings, gathered from a clinically relevant sample of heavy-drinking individuals with AUD, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.